PROJECT SUMMARY Our previous observations indicate that trauma victims who require artificial nutrition: 1) are likely to be undernourished during the first week after injury, 2) will often require intensive and costly support for organ failure, and 3) the amount of protein received may be an important determinant of clinical outcomes. A recent summit, convening experts concluded that we must study more thoroughly whether more protein is beneficial to critically ill patients. Determining whether and how to supplement protein intake is a critical unmet need. We have observed changes in response to injury and nutritional support that reflect suppression of protein metabolism in response to injury and a restoration of protein synthesis in response to enteral nutrition. In our studies, citrulline, an intermediate in nitrogen metabolism, stood out in our analyses as responsive to trauma and to enteral nutritional support. Citrulline is potentially relevant to a number of metabolic pathways related to protein synthesis which are important in critical illness and recovery and for these reasons, is the focus of two of our hypotheses; however, we have the opportunity to study a broad range of metabolites. We propose to recruit subjects who are enrolled in a randomized clinical trial of high dose enteral protein supplementation compared to subjects treated with standard enteral nutrition as part of an established, evidence-based approach to care. We will apply metabolomics and analytic methods to help us better understand the metabolic response to injury, and to understand how protein and other nutrients are metabolized in critically ill surgical patients and trauma victims. Our studies are innovative through the application of targeted metabolomic measurements of 200 circulating metabolic substrates and end-products, representing ~25 metabolic pathways in critically ill trauma and surgical patients over their stay in the intensive care unit. Our proposed aims are: (1) To determine the effects of early enteral protein supplementation on circulating markers of protein metabolism, (2) To determine whether we can predict urine nitrogen excretion using a combination of demographic, clinical and metabolite biomarkers; enabling us to more precisely prescribe enteral protein. Standard approaches to artificial nutritional support may not capture all the important differences that could be addressed through precision nutritional support. Our objective is to move us closer to this goal.